Development of stable, orally bioavailable small molecule positive modulators of HGF/MET signaling for the treatment of cognitive impairment.

Abstract

AbstractBackgroundPositive modulators of the HGF/MET system likely represent a valuable therapeutic class with the potential to impact a variety of disorders, including neurodegenerative diseases and indications with cognitive impairment. Preclinical and clinical studies have established the therapeutic potential of fosgonimeton (ATH‐1017), a small molecule injectable positive modulator of the HGF/MET system that is currently in clinical trials in patients with Alzheimer’s disease and Parkinson’s disease. At Athira Pharma, Inc., we have worked to expand the platform of HGF/MET positive modulators by identifying small molecules with a range of properties with the potential to meet therapeutic and delivery needs of patients across neurological diseases.MethodBuilding on the MET receptor augmentation activity of fosgonimeton, we designed a screening funnel to evaluate chemical variants with desired physiochemical properties. We synthesized a panel of small molecules intended to promote pharmacokinetic stability and tested each variant for in vitro activity via MET phosphorylation. Active molecules were then tested for in vitro stability, in vivo pharmacokinetics, and in vivo efficacy in a scopolamine‐induced spatial memory test.ResultWe identified a panel of molecules with novel chemistry, biochemical activity in vitro, and favorable physiochemical properties. Among these active molecules, several were selected to move into advanced testing. In pharmacokinetic evaluation, these molecules efficiently distributed to the brain and other target tissues following oral administration. Selected molecules were advanced to in vivo efficacy testing, which resulted in reversal of scopolamine‐induced spatial memory deficits in rats as assessed in the Morris water maze.ConclusionNovel, stabilized small molecule positive modulators of HGF/MET demonstrated procognitive effects following oral delivery. Further development of these compounds may have the potential to provide an array of administration options for patients with neurodegenerative or cognitive disorders.